气候变化领域集成服务门户(CCPortal): TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau

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DOI	10.1073/pnas.2014188118
	TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau
	Ash P.E.A.; Lei S.; Shattuck J.; Boudeau S.; Carlomagno Y.; Medalla M.; Mashimo B.L.; Socorro G.; Al-Mohanna L.F.A.; Jiang L.; Öztürk M.M.; Knobel M.; Ivanov P.; Petrucelli L.; Wegmann S.; Kanaan N.M.; Wolozin B.
发表日期	2021
ISSN	00278424
卷号	118 期号:9
英文摘要	Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Alzheimer's disease; Fibrillar tau; Liquid-liquid phase separation (LLPS); Oligomeric tau; RNA binding proteins
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180495
作者单位	Department of Pharmacology and Experimental Therapeutics, Boston University, School of Medicine, Boston, MA 02118, United States; Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, United States; Department of Anatomy and Neurobiology, Boston University, School of Medicine, Boston, MA 02118, United States; Department of Neurology, Boston University, School of Medicine, Boston, MA 02118, United States; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States; German Center for Neurodegenerative Diseases, DZNE, Berlin, 10117, Germany; Department of Translational Neuroscience, Grand Rapids Research Center, Michigan State University, Grand Rapids, MI 49503, United States; Center for Systems Neuroscience, Boston University, School of Medicine, Boston, MA 02118, United States; Neurophotonics Center, Boston University, School of Medicine, Boston, MA 02118, United States
推荐引用方式 GB/T 7714	Ash P.E.A.,Lei S.,Shattuck J.,et al. TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau[J],2021,118(9).
APA	Ash P.E.A..,Lei S..,Shattuck J..,Boudeau S..,Carlomagno Y..,...&Wolozin B..(2021).TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.Proceedings of the National Academy of Sciences of the United States of America,118(9).
MLA	Ash P.E.A.,et al."TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau".Proceedings of the National Academy of Sciences of the United States of America 118.9(2021).